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A pilot study to evaluate the effects of C1 esterase inhibitor on the toxicity of high-dose interleukin 2

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In a pilot study six patients received 4 days' treatment with interleukin 2 (IL-2) [cumulative dose (CD) 264 +/- 26 x 10(6) IU m-2] and C1 esterase inhibitor (C1-INH) (loading dose 2,000 U, followed by 500-1,000 U twice daily). Toxicity was
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  Br. J. Cancer (1994), 69, 596 598  . Macmillan  r ss Ltd 1994 SHORT COMMUNICATION A pilot study to evaluate the effects of Cl esterase inhibitor on the toxicity of high-dose interleukin 2 A.C. Ogilvie , J.W. Baars , A.J.M. Eerenberg2,C.E.Hack2, H.M. Pinedol, L.G. Thijs3   J. Wagstaff 'Departmentof Medical Oncology, Free University Hospital, Amsterdam, The Netherlands; 2Department of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Blood Transfusion Services, Amsterdam, The Netherlands; 3Medical Intensive Care Unit, Free UniversityHospital, Amsterdam, The Netherlands. Summary In a pilot study six patientsreceived 4 days treatment with interleukin 2 (IL-2) [cumulative dose (CD) 264 ± 26 x 106 IU m2] andCl esterase inhibitor (C1-INH) (loading dose 2,000 U, followed by500- 1,000 U twice daily). Toxicity was compared with that in patients given 4 days treatment withstandard (CD 66 ± 12 x 106 IU m-2) or escalating-dose (CD 99 ± 8 x 106 IU m-2) IL-2. IL-2-induced hypotension was equivalent andcomplement activation was less after IL-2 + C1-INH (C3a = 10.5 ± 3.2 nmol -l1 than follow-ing standard (14.1 ± 8.4 nmol l') or escalating-dose (18.3 ± 2.9 nmnol' ) IL-2. This study demonstrates that Cl -INH administration duringIL-2 treatment is safe and warrants further study to evaluate its ability to ameliorate IL-2-induced toxicity. Although interleukin 2 (IL-2) has proved to be an effective therapy for some renal cell carcinoma and melanoma patients, its utility has been limited by toxicity. Dose-limiting toxicityconsists of hypotension and damage to small blood vessels, leading to a capillaryleak syndrome characterised by fluid retention and weight gain. The severity of the toxicity is proportional to the IL-2 dose administered. During IL-2 therapy the complement system becomes activated (Thijs et al., 1992; Moore et al., 1991; Vachino et al., 1991; Baars et al., 1992; Clayman et al., 1992). This activation is dose dependent (Thijs et al., 1990; Baars et al., 1992), occurs via several pathways including the classical route (Thijs et al., 1990; Moore et al., 1991; Vachino et al., 1991), and correlates with the degree of hypotension induced (Baars et al., 1992) and parameters of capillary leakage (Thijs et al., 1990; Baars et al., 1992). The classical route of complement activation is regulated byCl esterase inhibitor (C1-INH). In a preliminary study the administration of human C1-INH to patients with septic shock appeared to be safe and was probably associated withattenuation of complement activa- tion (Hack et al., 1992). In this pilot study we have inves- tigatedthe feasibility of using C1-INH to ameliorate the hypotension induced by high-dose IL-2. Patients andmethods Six patients (Table I received a 1 h infusion of C1-INH [2,000 units (U), Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Amsterdam,The Nether- lands] immediately prior to the first IL-2 infusion, and this was repeated at a dose of 500 or 1,000 U every 12 h thereafterfor 4 days. IL-2 (EuroCetus, Amsterdam, The Netherlands) was given at a dose of 72 x 106 IU m-2 day-' for 4 days (theexperi- mental course). Three weeks after the experimental course and following theresolution of all toxicity, the same patients received a second cycle of IL-2 at a standarddose of 18 x 106 IU m2 day-' for 4 days butwithout C1-INH  self- control course). Data from thesepatients were compared with those from fourother patients (Table I who had previously received IL-2 at escalating doses of 18-36 x 106 IU m-2 day- alsofor 4days (historical-control course). All IL-2 was given by a 15 min infusion. The experi- mental and historical-control courses were administered in the intensivecare department, and both groups received parenteral nutrition. The self-control course was given in the high-care section of the OncologyDepartment butwithout parenteral nutrition. Hypotension (systolic blood pressure >95 mmHg) was treated initially with plasma expanders andwhere necessary with dopamine or noradrenaline. Blood samples for measurementof C1-INH and comple-ment components wereobtained and stored as previously described (Nuijens et al., 1989). Total plasma C1-INH wasmeasured with a nephelometer (Behring Werke Nephelometer Analyzer, Behring Werke) and expressed as a percentage of normalby reference to pooledplasma from normal blooddonors (normal values 70-134 ). Plasma C3a (levels > 5nmol 1-1 are elevated) was measured witha competitive radioimmunoassay (Hack et al., 1988). Results were expressed as meansand standard deviations. Comparisons within and betweengroupswere doneby using a paired Student t-test. Proportionswere compared by using Fisher sexact test. P-values <0.05 were considered statis- Table I Patient characteristics CumulativeIL-2 doses Age (years), Experimental Self-control sex Diagnosis coursecourse Pilot study group 49, M Renal cell carcinoma23472 57, M Renal cell carcinoma288 72 43, M Melanoma 28872 46, F Renal cell carcinoma 28836 55, M Melanoma 27072 54, F Melanoma 21672 Historical-control group 35, M Melanoma 108 57, M Renal cell carcinoma90 51, M Melanoma 10840, M Melanoma 90 M, male; F,female. ax 106IUm-2 over 4 days. Correspondence: J. Wagstaff, Department ofMedical Oncology, Free University Hospital, De Boelelaan 1117, 1081 HV Amsterdam,The Netherlands. Received 10 September 1993; and in revised form 2 November 1993. 12 Macmillan Press Ltd., 1994 r. J. Cancer  1994 , 69, 596-598  Cl ESTERASE INHIBITOR ADMINISTRATION DURING IL-2 THERAPY 597 C 0 .0 E 0 4 - c 0 0003a0 0 10 0 0 0 120 100 80 69 40 50 40 w E C co 30 20 10 0   00 0 0 50 100 150 200 Cumulative IL-2(IU m-2) 250 Figure 1 Changes in mean blood pressure a, and in plasma C3a levels b, during IL-2therapy plotted against the cumulative doseof IL-2 administered. The plottedvalues are those measured immediately beforeIL-2administration. Blood pressure is ex- pressed as a percentage from baseline values. 0 O, experi- mental course (IL-2 + Cl -INH); A ---A, self-controlcourse; O ---0, historical-control course. tically significant. Mean blood pressure was derived from the sum of one-third systolic blood pressure and two-thirds dias- tolic blood pressure. Changes in blood pressure betweengroups were analysed by using the percentages of the baseline values. The slope of linear trend in the measured variables plottedagainst the cumulative doseof IL-2 administered was determined with the linear regressiontechnique. Results The cumulative IL-2doses given during the experimental course (264 ± 26 x 106 IU m-2) were significantly higher than those during either the self- (66 ± 12 x 106 IU m2) or historical- (99 ± 8 x 106 IU m-2) controlcourses. Because the C1-INH plasma levels of the first patient did not exceed 152 after 24 h, C1-INH was given in doses of 1,000 U every 12 h instead of 500 U thereafter. The mean blood pressure decreased from 94± 8 to 77 ± 14 mmHg during the experimental course. This fall was not significantly different from that seen during the self- control course (98 ± 13 to 89 ± 10 mmHg) or the historical- control course (89 ± 8 to 85 ± 8 mmHg). During the experi- mental course the decrease in mean blood pressure plotted against the administered IL-2 dose was less than that of theself-control course (slope of linear trend -0.08 vs -0.15) and similar to that observed during the historical-control course (slope of linear trend   0.08) (Figure la). Vasopres- sors were administered during an equivalent number of patient days during the experimental and the historical- a control courses(10/23 vs 6/10 respectively). There was an equivalentgain in body weight during the experimental and thehistorical-control courses, + 5 + 2.6 vs + 3.6 ± 1.3 , both significantly greater thanduring the self-control course (weight change -0.2 ± 1.7 ). Thiso difference was due to the greater fluid load from parenteral nutrition rather than a more severe capillary leak syndrome alone. O°. Baseline plasma C3a values were in the normal range and o did not differ significantly between courses. During the exper- imental and self-control courses C3a rose to a similar degree (10.5 ± 3.2 and 14.1 ± 8.4 nmol  l at 96 h respectively) but was significantly lower than after the historical-control course (18.3 ± 2.9 nmol 1 ). The increase in plasma C3a levels plot- ted against the administered IL-2 dose was less during the experimental course (slope of linear trend 0.02) than during b the self-control and historical-controlcourses (slope of linear trend0.12 and 0.14) (Figure Ib . During the administration of C1-INH no side-effects were observed. C1-INH administration caused a significant inc- rease in the plasma levels of total C1-INH from 128 ± 28 to 166 ±39 immediately before the start of the IL-2 infusion in the experimental course. Total C1-INH increasedgradually thereafter to 195 ± 33 after 96 h. During the self-control course total C1-INH did not change significantly (148 ± 47 to 136 ± 19 ). In the historical controls total Cl- INH remained at baseline levels during the first two treat- o ment days and thereafter it increased from 124 ± 16 to o 178 ± 17 at 96 h after the start of IL-2.300 Discussion These results demonstrate that in the patients who received high doses of IL-2 (72 x 106 IU m2 day- ) together with C1-INH administration the degree of complement activation was similar to that achieved when a subsequent course of IL-2 was given at four times lower cumulative dose (18 x 106 IU m-2 day- ) butwithout additional C1-INH (see also Table I . Moreover, toxicity induced by the experimental course of high-dose IL-2 and C1-INH administration wasno more severe than that observed in a historical-control groupwhich had received a 2.7 times lower cumulative doseof IL-2. In addition, no toxic side-effects of C1-INH treatment were observed. Considering that IL-2 induces complement activation in a dose-dependent manner, our observations are consistent with the hypothesis that C1-INH administration can inhibit comp- lement activation during IL-2 treatment and thus presumably ameliorate IL-2-induced toxicity. C1-INH administered ac- cording tothis protocol was not associated with complete inhibition of complement activation. The data may indicatethat optimalisation of the C1-INH dose and schedule, result- ing in a 2-fold elevation of the C1-INH plasma level, might result in a greaterinhibition of complement activation and thereby further reduce IL-2-related toxicity. Modulation of early mediators of IL-2 toxicity, such as tumour necrosis factor (TNF), can also result in reduced toxicity (Mier et al., 1990). Thedexamethasone used to achieve suppression of TNF release was, however, associated with undetectable NK activity in those patients and with the lack of objective regressions in another study (Vetto et al., 1987). Administration of C1-INH does not seem to interfere with IL-2-induced NK and LAK cytotoxicity either in vitro or in vivo in the experimental course (data not shown). Furthermore the anti-tumour effects of IL-2 are not com- pletely inhibited because one partial remission was observed in thecurrent study. Modulation of later mediators of tox- icity such as complement may, therefore, be preferable. The results from this open label pilot study warrant a further double-blind randomised controlled trial of Cl-INH administration during high-dose IL-2 immunotherapy.  598 A.C. OGILVIE et al. References BAARS, J.W., HACK, C.E., PINEDO, H.M., EERENBERG-BELMER, A.J.M., WOLBINK, G.J., THIJS, L.G., STRACK VAN SCHINDEL, R.J.M., VANDER VALL, H.L.J.A.   WAGSTAFF, J. (1992). The activation of polymorphonuclear neutrophils and the complement systemduring immunotherapy with recombinant interleukin-2.Br. J. Cancer, 65, 96-101. CLAYMAN, G.L., LIU, F.J., SAVAGE, H.E., TAYLOR, D.L., LAVEDAN, P., BUCHSBAUM, R.M., PELLEGRINO, C., TRUJILLO, J.M., YOUNG, G.   SCHANTZ, S.P. (1992). Acute-phase proteins in patients with head and neck cancer treated with interleukin-2/interferon alfa. Arch.Otolaryngol. Head Neck Surg.,118, 41-48. HACK, C.E., PAARDEKOPER, J., EERENBERG, A.J.M., NAVIS, G.O., NIJSTEN,M.W.N., THIJS, L.G.   NUIJENS, J.H. (1988).   modified competitive inhibition radioimmunoassay forthe detection ofC3a. Use of1251-C3a instead of 1251-C3a. J. Immunol.Methods, 108, 77-84. HACK, C.E., VOERMAN, H.J., EISELE, B., KEINECKE, H.-O., NUI- JENS, J.H., EERENBERG-BELMER, A.J.M., OGILVIE, A., STRACK VAN SCHINDEL, R.J.M., DELVOS, U.,   T IJS L.G.(1992). Cl- esterase inhibitorsubstitution in sepsis. Lancet,339, 378. MIER, J.W., VACHINO, G., KLEMPNER, M.S., ARONSON, F.R., NOR- ING, R., SMITH, S., BRANDON, E.P., LAIRD, W.   ATKINS, M.B. (1990). Inhibition of Interleukin-2 induced tumour necrosis factor release by dexamethasone: Prevention ofan acquired neutrophil defect and differential suppression of IL-2 induced side effects. Blood, 76, 1933-1940. MOORE Jr, F.D., SCHOOF, D.D., RODRICK, M.   EBERLEIN, T.J. (1991). The systemic complement activation caused by interleukin-2/lymphokine-activated killer-cell therapyof cancer causes minimal neutrophil activation. Int.J. Cancer, 49, 504-508. NUIJENS, J.H., EERENBERG-BELMER, A.J.M., HUIJBERGTS, C.C.M., SCHREUDER, W.O., FELT-BERSMA, R.J.F., ABBINK, J.J., THIJS, L.G.   HACK, C.E.(1989). Proteolyticinactivation of plasma Cl inhibitor in sepsis. J. Clin.Invest., 84, 443-450. THIJS, L.G., HACK, C.E., STRACK VAN SCHIJNDEL, R.J.M., NUIJENS, J.H., WOLBINK, G.J., EERENBERG-BELMER, A.J.M. VANDER VALL, H.L.J.A.   WAGSTAFF, J. (1990). Activation of the comple- ment systemduring immunotherapy with recombinant IL-2. J. Immunol., 144, 2419-2424. VACHINO, G., GELFAND, J.A., ATKINS, M.B., TAMERIUS, J.D., DEMACHAK, P.   MIER, J.W.(1991). Complement activation in cancer patients undergoing immunotherapy with interleukin-2: Binding of complementand C-reactive protein by IL-2 activated lymphocytes. Blood, 78, 2505-2513. VETTO, J.T., PAPA, M.Z., LOTZE, M.T., CHANG, A.E.   ROSENBERG, S.A. (1987). Reductionof toxicity of Interleukin-2 and lym- phokine activated killercells in humans by the administration of corticosteroids. J. Clin. Oncol., 5, 496-503.
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